Orally administered drug composition for therapy in the treatment of narcotic drug addiction

ABSTRACT

Drugs which are suitable for such therapy in treatment of narcotic drug addiction by oral use, e.g., methadone, are formulated to prevent injection abuse through concentration of the active component in aqueous solution by incorporating in a solid dosage or tablet form of such drug an ingestible solid precipitating agent for said active component, preferably in association with at least one ingestible solid having thickening properties which causes rapid increase in viscosity upon concentration of an aqueous solution thereof. Formulating alkali insoluble amine-containing drugs in a dosage form that provides an alkaline reaction serves to inhibit its abuse.

United States Patent [191 Shaw et al.

[451 May 20, 1975 1 ORALLY ADMINISTERED DRUG COMPOSITION FOR THERAPY INTHE TREATMENT OF NARCOTIC DRUG ADDICTION [75] Inventors: Irving F. Shaw,East Rockaway',

Jerome Berk, New Rochelle, both of 21 Appl. No.: 387,712

Related US. Application Data [63] Continuation-in-part of Ser. No.133,344, April 12,

1971, abandoned.

3,773,955 11/1973 Pacter et al 424/260 OTHER PUBLICATIONS Merck Index,8th Edition (1968), pp. 669, 964 and 1012.

Wilson et al., Textbook of Organic Medicinal and PharmaceuticalChemistry, 1962, pp. 237, 238, 566, 567,569,570, 580, 581.

Primary Examiner-Albert T, Meyers Assistant Examiner-Norman A. DrezinAttorney, Agent, or Firm-Robert I. Pearlman [5 7] ABSTRACT Drugs whichare suitable for such therapy in treatment of narcotic drug addiction byoral use, e.g., methadone, are formulated to prevent injection abusethrough concentration of the active component in aqueous solution byincorporating in a solid dosage or tablet form of such drug aningestible solid precipitating agent for said active component,preferably in association with at least one ingestible solid havingthickening properties which causes rapid increase in viscosity uponconcentration of an aqueous solution thereof. Formulating alkaliinsoluble amine-containing drugs in a dosage form that provides analkaline reaction serves to inhibit its abuse. I

13 Claims, No Drawings 1 ORALLY ADMINISTERED DRUG COMPOSITION FORTHERAPY IN THE TREATMENT OF NARCOTIC DRUG ADDICTION CROSS REFERENCE TORELATED APPLICATIONS This application is a continuation-in-part of Ser.No. 133,344, filed Apr. 12, 1971 for the instant inventors, nowabandoned.

BACKGROUND OF THE INVENTION In attempting to combat the problem ofnarcotic ad diction and particularly addiction to heroin, consider ableattention has been given in recent years to oral administration of drugswhich have the effect of greatly reducing or abolishing narcotic hungerand blocking the euphoriant action of the heroin or other addictivedrugs. Particularly encouraging results have been achieved when usingthe drug methadone in the form of the free base or acid salts thereofsuch as methadone hydrochloride. While methadone itself has someaddictive tendencies when administered orally, it does not haveeuphoriant properties and has been found effective when treating addictsin blocking both narcotic hunger and the euphoriant action of otheraddictive drugs.

The accepted procedure in the oral administration of methadone or itsacid salts has been to incorporate the same into a powder or watersoluble tablets of dosage unit size, dissolving in a small quantity oforange juice or other fruit juice and having the patient drink thisjuice solution. The effectiveness of treatment is largely dependent uponan established treatment schedule being adhered to; and when treatingout-patients, they are provided with a limited number of doses withspecific instructions as to frequency of use.

In preparing tablets containing methadone or its acid salts for use inthe manner described, it has been the practice to provide a readilywater soluble composition so that the powder or tablets can be quicklyand easily dissolved in fruit juice for administration. A problem withpowders or tablets of the type heretofore available, however, is thatthey can also be dissolved in plain water to provide a solution whichcan be filtered fairly easily, and concentrated by evaporation toproduce an aqueous residue sufficiently rich in methadone to beattractive to addicts when administered by injection as a substitute fortheir habitual addictive drugs. Drug addicts have been quick torecognize this possibility and the need for guarding and policingsupplies of methadone and its acid salts have tended to limit the moreextended use of these drugs in oral maintenance therapy.

Conventional methadone hydrochloride tablets are also potentiallyhazardous if a quantity of tablets are accidentally ingested. In fact,several fatalities have been reported due to out-patients supplies ofmethadone hydrochloride being found and ingested by children.

THE INVENTION The new compositions of the present invention and theirunique and advantageous properties are best visualized as they developedchronologically.

In attacking the problems above mentioned, it appeared that ingestiblesolids having thickening capability as components of a drug compositionfor maintenance therapy could help prevent injection abuse by increasingviscosity of a solution of a composition during attempted evaporation sothat separation of the therapeutic agent in sufficiently concentratedform to permit'its use by injection would become extremely difficultwithout highly specialized equipment. Furthermore, it appeared that theincorporation of a disintegrating agent such as sodium bicarbonate and asolid ingestible acid would have the dual advantage of acceleratingdissolution of tableted composition for oral administration by thecustomary procedure, i.e., dissolved in orange juice or the like, and atthe same time minimize the chance of accidental ingestion because of theunpleasant sensation an effervescent tablet would create in the mouth,

In formulating compositions containing these two types of additives, anexcess of the sodium bicarbonate was used, i.e., more than necessary toreact with the ingestible acid, since any excess could react with thefruit juice when the composition was prepared for oral administration.Tablets prepared in this way using methadone hydrochloride as thetherapeutic agent were found to have effectiveness in the treatment ofdrug addicts comparable to conventional tablets containing the sameamount of methadone hydrochloride.

That is, in checking out the effectiveness of the thickening componentas a means for preventing injection abuse, tablets were dissolved inwater and the solution then heated to evaporate part of the water. Asthe evaporation progressed, there was an expected increase in viscosityof the solution but at the same time an unexpected lowering of themethadone level in the solution. Further investigation revealed thatheating of the solution with evolution of carbon dioxide from the sodiumbicarbonate caused the pH to drift progressively higher, and that thiswas responsible for a precipitation of methadone during evaporation ofthe solution.

Separate investigation into the solubility of methadone in the generalpH range of 6 to 9 gave results as shown in the following tabulation:

SOLUBILITY OF METHADONE CALCULATED AS THE HYDROCHLORIDE In thisconnection, it should be noted that one attempting to achieve a high byinjection of methadone solution will need about 20 mg of methadone in lto 5 ml of water. From the above table, it will appear that at a pH of 7or lower, an aqueous solution of sufficient strength for injection toachieve a high can be prepared, but above pH 7 it becomes increasinglydifficult to prepare a solution of sufficient strength and at a pH above7.50 the solubility of methadone becomes so low as to completelyfrustrate its improper use by inection.

In view of the foregoing, it is to be understood that the basic noveltyof the present invention resides in incorporating, in a drug formulationfor oral administration in maintenance therapy, in treatment of narcoticaddiction, a component which will induce precipitation of a majorportion of the therapeutic agent if the composition is dissolved inwater and the solution is then concentrated, while at the same timepermitting full dissolution in orange juice or comparable acidic mediawhich do not permit of injection. Essentially, the reduced solubilitymay be attained either by a composition which produces a pH of about 7.5to 10 directly upon dispersion in water, or by a composition which uponinitial dispersion produces a pH of at least 6 which then increases topH 7.5 or more upon concentration; or by a component which will form asalt with the therapeutic agent which is soluble at an acidic pH but hasmarkedly reduced solubility at a substantially neutral or alkaline pH.

Typical ingestible solids which provide an alkaline pH in aqueoussolution include soluble alkali metal and alkaline earth metalcarbonates, bicarbonates, phosphates, and acid phosphates. Of these, thebicarbonates, and particularly sodium bicarbonate, are consideredpreferable since, as earlier mentioned, the evolution of CO duringheating of an aqueous solution causes the pH to drift progressivelyhigher during attempts at evaporation.

When Nal-lCO is used as the pH regulating additive, additional amountscan be employed together with a stoichiometrically equivalent amount ofa solid food acid, such as tartaric acid and the like. In such cases, asubstantial excess of bicarbonate to food acid (equivalent ratio ofbicarbonate/acid) is employed, e.g., 1.89/1 (Example III) to 2.44/1(Example 1V) so that substantial bicarbonate remains available forproviding alkaline conditions so as to insolubilize the aminecontainingtherapeutic agent. Typically, an equivalent bicarbonate/acid ratio of atleast 1.5 should be used.

Typical examples of ingestible solids which can form insoluble salts ofthe therapeutic agent at a substantially neutral or alkaline pH while atthe same time being soluble at an acid pH are alkaloid precipitatingagents such as tannic acid and picrolonic acid. When the compositioncontains this type of additive for reducing solubility of thetherapeutic agent in water, it can still be advantageous to employ adisintegrating agent, suitably in the form of sodium bicarbonate incombination with a solid food acid as above described.

The amount of pH controlling component to be incorporated in thecomposition will vary to some extent with the particular therapeuticagent and the intended dosage thereof. By way of illustration, whenmethadone hydrochloride is the therapeutic agent, a tablet or othersolid dosage unit, generally containing 40 mg of methadonehydrochloride, is dissolved in about 3 to 4 ounces of water, orangejuice of other acidic (pH 5 or lower) drink before being taken by thepatient. On the other hand, a person seeking to recover an injectableform of methadone from such solid dosage form would dissolve the same ina minimum amount of water, probably less than ml since larger amounts ofwater would merely complicate efforts to concentrate the drug. Thus, theamount of pH controlling agent per solid dosage unit should besufficient to provide the desired pH control when a dosage unit isdissolved in about 10 ml of water.

A component which acts, instead, by forming an insoluble salt at asubstantially neutral pH should be present in at least thestoichiometric amount to react with 4 the methadone or other therapeuticagent in the composition.

While the components above described are themselves sufficient togreatly deter efforts to recover the therapeutic agent in forms suitablefor injection, it is preferable in forming compositions and tablets inaccordance with the invention to incorporate in addition one or moreadditives which have the effect of deterring concentration by causing arapid increase in viscosity during evaporation of an aqueous solution ofthe composition. For this purpose various ingestible solids havingthickening capability can be employed including for example sugars orsugar derived alcohols, such as lactose, sucrose, mannitol, sorbitol,and the like, and polymeric materials, such as starches,microcrystalline cellulose, sodium carboxymethyl cellulose,methylcellulose, ethyl cellulose, carrageenin, gum tragacanth, gumacacia, polyvinylpyrrolidone, etc. Such additives or adjuvants arepreferably present in the proportion of about 0.5 to 1.5 grams pertablet containing the normal unit dose of therapeutic agent (40 mg inthe case of methadone hydrochloride). Expressed in another way, theweight ratio of this type of additives to the therapeutic agent shouldbe in the range of about 10 to 1 to 40 to 1.

With these ingestible solid additives or adjuvants present in thecomposition, attempts at evaporation of an aqueous solution in an effortto produce an aqueous concentration of the therapeutic agent, sufficientto produce a high upon injection, will produce a highly viscousconcentrate incapable of being handled by a syringe.

While each of the type additives above described can be usefulindividually in curbing the misuse of drug compositions prepared fororal administration in maintenance therapy, it must be borne in mindthat the drive of drug addicts to satisfy their hunger for drugs canmake them extremely resourceful in devising means of preparing aninjection. For this reason, it is desirable to employ a plurality ofdeterrents. Preferred compositions will include, in addition to themethadone or other drug, at least one pH control or salt formingcomponent which will precipitate the therapeutic agent, and one or moreof the viscosity control components or thickening agents.

In the preparation of tablets or other dosage units of the drugs, itwill be understood that, in addition to the special additives oradjuvants above described, there will be present the normal type ofsolid adjuvants including agents such as zinc stearate which facilitatemold release in the formation of tablets. Adjuvants of the compositioncan also include conventional coloring agents and/or flavoring agents.It is considered preferable, however, to omit flavoring agent since thebitterness imparted by the therapeutic agent further tends to discourageaccidential ingestion, while being offset during administration by thefruit juice or other acidic drink normally employed for dissolving thedrug in maintenance therapy in treatment of narcotic drug addiction.

The following examples will provide a fuller understanding of theinvention, but it is to be understood that these examples are given byway of illustration and not of limitation:

EXAMPLE I The ingredients and manufacturing method for producing a batchof about 20,000 methadone hydrochloride tablets are given below:

Methadone Hydrochloride USP Powder The indicated quantities of methadonehydrochloride, mannitol, lactose, corn starch, polyvinylpyrrolidone, andtartaric acid are mixed until homogeneity is achieved. The properquantity of granulating solution consisting of 50 percent methanol and50 per cent demineralized water is added. The resulting wetted mass isscreened and evenly spread on paper lined trays, and dried at 100-1 F insuitable ovens. Drying is considered complete when the moisture contentis less than 0.5 percent maximum. The material is then screened again.This screened mass is weighed and then transferred to a mixing vessel towhich are added the proper quantities of methylcellulose,ethylcellulose, zinc stearate, microcrystalline cellulose; finallyenough sodium bicarbonate is added to bring the mass to the requiredtotal weight. This is then mixed until homogeneity is achieved. Theresultant mixture is assayed and then transferred to a compressingmachine on which tablets are produced in accordance with thespecifications, to contain 40 mg of methadone hydrochloride.

The same formula can be prepared in powder form with or without the zincstearate by simple mixing without granulating. Alternatively, thegranules can be prepared for dispensing as such by omitting thecompression procedure. Tablets containing from 5 to 100 mg of methadonehydrochloride can be formed from the identical composition according totherapeutic need.

A tablet, prepared as above described, when placed in about 4 ounces oforange juice, effervesces spontaneously and disintegrates completelywithin about 3 minutes. assure stirring will speed disintegration andassures a uniform suspension. Drinking of a suspension thus prepared bya patient on maintenance therapy is found to be equally as effective assimilar suspensions made with 40 mg of U.S.P. methadone hydrochloride orother commercially available 40 mg tablets.

One tablet containing 40 mg was added to 4 ounces of water (about 120ml) at room temperature. The tablet was permitted to effervescespontaneously. Dispersion was complete within 3 minutes. The suspensionwas stirred to make it essentially uniform and passed through a Whatmannumber 31 filter paper until the filtrate was clear. The pH of thefiltrate was 6.7. Analysis showed approximately 0.35 mg/ml methadonehydrochloride, substantially the theoretical amount. This very dilutesolution could be passed through a syringe, but would be of little valuefor illicit parenteral administration because of the extreme dilution.

The filtered solution was then concentrated by evaporation in a constantstream of air with gentle heating by means of a hot plate. When thevolume of the solution was brought down to ml, correspondinghydrochloride a theoretical, methadone hydrochloride, content of 2mg/ml, a sludge of amorphous material formed in the container. Analysisshowed practically no methadone hydrochloride in the liquid portion,less than 0.1 mg/ml. The pH of the filtrate was 8.8.

It is significant that the excess of sodium bicarbonate in thecomposition of this example, e.g. an equivalent ratio of bicarbonate totartaric acid of 2.27/1, permitted a substantially neutral pH at theinitial dissolution, permitting the methadone to remain in dilutesolution when the tablet was dissolved in water. However, attempts toconcentrate the solution caused the indirect effect of raising the pH.This use of the latent alkalinity of sodium bicarbonate to prevent abusein replacement therapy is a prominent feature of this invention. Withincreased excess of sodium bicarbonate if desired, it is possible torender the methadone less soluble, so that filtered solutions willimmediately show reduced methadone content.

Another tablet containing 40 mg of methadone hydrochloride was added to10 ml of water. In this case, the disintegration time increased comparedwith the use of ml of water. Upon stirring the solution and allowing itto settle (the settling took several hours), 8 ml of turbid solutioncould be withdrawn. The analysis of this solution showed less than 0.1mg/ml of methadone.

By way of comparison, a commercial tablet, salmon colored, quadrisected,containing 40 mg methadone hydrochloride, and weighing 1.70 grams wasplaced in 120 ml of water. The tablet expanded in volume and dissolvedslowly in water leaving a fine sediment at the bottom of the container.The pH of the solution was 5.3; this pH remaining constant over severalminutes. The solution was filtered through an analytical grade of filterpaper, leaving a heavy orange residue containing practically nomethadone. The filtrate was carefully evaporated on a hot plate to 10percent of its volume, during which time the pH decreased to 5.1.Further evaporation gave an orange film, weighing 0.16 gram. The filmwas soluble in 2.5 ml of water to give an opaque orange solution, pH4.6, containing the 40 mg of methadone, an unapproved injectablepharmaceutical form.

The acute oral toxicity of the methadone hydrochloride in thecomposition of Example I is found to be significantly lower than theacute oral toxicity of methadone hydrochloride U.S.P.

EXAMPLE II A tableting formulation of methadone hydrochloride isprepared using the following ingredients and formed into tablets eachcontaining 40 mg of methadone hy-- drochloride:

Methadone HCl 0.5 parts Lactose 6.0 do. Mannitol 2.0 do. Corn Starch 2.5do. Disodium Phosphate 0.25 do. Sod. carboxymethylcellulose 0.5 do.Methyl Cellulose 0.5 do. Sod. Saccharin 0.2 do. Zinc Stearate 0.75 do.

A tablet thus prepared was dispersed in 120 ml of distilled water andgave a pH of 7.8. Upon filtration and concentration to 10 ml, a viscousgummy mass resulted, of substantially the same pH. The concentratedsolution could not be drawn up into a syringe with a number 18 needle.Analysis of a drop of clear liquid that separated from the gummy massshowed less than 1 mg/ml methadone.

Tablets of this composition disperse readily in 4 oz. of orange juice,with complete methadone solubility. The same formula can be suitablyused to prepare a capsule dosage form.

EXAMPLE III A tableting composition similar to that described in ExampleI but including 2400 gm of tannic acid, i.e., three times the weight ofmethadone hydrochloride, was prepared and formed into 40 mg tablets. Thetablet then had an equivalent ratio of bicarbonate/acid (tannic andtartaric acid) of 1.89/1.

When one of these tablets (containing 40 mg of methadone hydrochlorideand 120 mg of tannic acid) was dispersed in 120 ml of water, andfiltered, the pH was 6.7, and the filtrate contained about 0.02 mg ofmethadone hydrochloride per ml. The theoretical amount should be about0.33 mg per ml. indicating substantial removal from solution.

When another of these tablets was dissolved in 4 oz. of orange juice, pH4, and filtered, the solution analyzed 0.33 mg/ml methadone I-ICl, thetheoretical amount, indicating that availability in acid solution wasunimpaired.

EXAMPLE IV Another chemical compound which has found some use as a drugin maintenance therapy is propoxyphene (4-dimethylamino-3-methyll,2-diphenyl-2-butanol propionate). The solubility characteristics ofpropoxyphene are favorable for pH control, as shown below:

SOLUBlLlTY OF PROPOXYPHENE CALCULATED AS THE HYDROCHLORIDE pH Solublemg/lO ml A tableting composition was prepared, using the followingingredients, and formed into tablets each containing 100 mg ofpropoxyphene hydrochloride and an equivalent ratio of bicarbonate/acid(tartaric) of 2.44/1:

A tablet was dissolved in 120 ml water and gave a pH of 6.5. Thesolution was filtered and analyzed for propoxyphene. The filtratecontained the approximate theoretical amount, 0.8 mg/ml. The filtratewas then evaporated at low temperature with the aid of a stream of air,causing the pH to rise rapidly. When half the water was gone the pH was80.7. When only 10 ml of water was left, the pH was 9.0. Analysis showedthat the concentration of propoxyphene in solution when only 10 ml ofsolution remained, was substantially nil, less than 0.1 mg/ml. In otherexperiments in which the solution was evaporated by heating alone or byallowing to stand at room temperature alone, similar results wereobtained, indicating that the method used to concentrate the solutiondid not affect the results significantly.

Tablets containing from 25 to 200 mg of propoxyphene hydrochloride canbe formed from the identical composition according to the therapeuticneed.

While the disclosure has been aimed primarily at maintenance therapy inthe treatment of narcotic drug addiction, the ultimate goal ofwithdrawal can also be served by means of anti-addiction and antagonisttreatment. The same principles taught herein can be used to formulateanti-addiction or antagonist drugs such as naloxone, cyclazocine, andthebaine, for example, thereby insuring that the compositions be usedfor therapy by oral administration.

Other therapeutic agents in addition to those described herein may befound useful in the treatment of narcotic drug addiction, and it is tobe understood that the principles of the present invention for deterringinjection abuse by incorporating a precipitating agent, or precipitatingand thickening agents in the composition can be employed with otheramine (or substituted amine) containing therapeutic agents useful in thetreatment of narcotic drug addiction, the hydrochloride salt form ofwhich are soluble in water but essentially insoluble in alkalinesolution.

Various changes and modifications in the compositions herein disclosedmay occur to those skilled in the art, and to the extent that suchchanges and modifications are embraced by the appended claims, it is tobe understood that they constitute part of the present invention.

What is claimed is:

1. A solid composition for the oral treatment of narcoticaddiction whichis dispersible for dissolution in an acidic medium before ingestion,said composition comprising:

a. an effective amount of amine-containing therapeutic agent for themaintenance therapy treatment of narcotic drug addiction, thehydrochloride salt form of which is soluble in water but essentiallyinsoluble in alkaline solution,

b. a precipitating agent selected from the class consisting of:

1. an ingestible solid alkalinizing agent in an amount which provides analkaline pH of at least 7.5 when dissolved in water either directly, orindirectly upon heating or concentration of the solution,

2. an ingestible alkaloid precipitating substance selected from thegroup consisting of tannic acid and picrolonic acid in an amount activeas a precipitant in non-acidic conditions, and

3. combinations of (l) and (2).

2. The composition of claim 1, wherein said therapeutic agent ismethadone or its acid salts.

3. The composition of claim 1, wherein the precipitating agent is analkalinizing agent, and is present in an amount to achieve a pH withinthe range of 7.5 to 10 when said composition is dissolved in water.

4. The composition of claim 3, wherein said alkalinizing agent is Na HPO5. The composition of claim 1, wherein the precipitating agent is analkalinizing agent which provides a pH in water solution of at least 6,and causes an increase of pH to at least 7.5 upon heating orconcentration of the solution.

6. The composition of claim 5, wherein said alkalinizing agent is NaHCO7. The composition of claim 6 which also contains a solid food acid, theequivalent ratio of NaHCQ, to acid being substantially greater than 1.

8. The composition of claim 7, wherein the equivalent ratio of NaHCO toacid is at least 1.89/1.

9. The composition of claim 1, which further concontains 40 mg ofmethadone hydrochloride.

1. A SOLID COMPOSITION FOR THE ORAL TREATMENT OF NARCOTIC ADDICTIONWHICH IS DISPERSIBLE FOR DISSOLUTION IN AN ACIDIC MEDIUM BEFOREINGESTION, SAID COMPOSITION COMPRISING: A. AN EFFECTIVE AMOUNT OFAMINE-CONTAINING THERAPEUTIC AGENT FOR THE MAINTENANCE THERAPY TREATMENTOF NARCOTIC DRUG ADDICTION, THE HYDROCHLORIDE SALT FORM OF WHICH ISSOLUBLE IN WATER BUT ESSENTIALLY INSOLUBLE IN ALKALINE SOLUTION, B. APRECIPITATING AGENT SELECTED FROM THE CLASS CONSISTING OF:
 1. ANINGESTIBLE SOLID ALKALINIZING AGENT IN AN AMOUNT WHICH PROVIDES ANALKALINE PH OF AT LEAST 7.5 WHEN DISSOLVED IN WATER EITHER DIRECTLY, ORINDIRECTLY UPON HEATING OR CONCENTRATION OF THE SOLUTION,
 2. ANINGESTIBLE ALKALOID PRECIPITATING SUBSTANCE SELECTED FROM THE GROUPCONSISTING OF TANNIC ACID PICROLONIC ACID IN AN AMOUNT ACTIVE AS APRECIPITANT IN NON-ACIDS CONDITIONS, AND
 2. an ingestible alkaloidprecipitating substance selected from the group consisting of tannicacid and picrolonic acid in an amount active as a precipitant innon-acidic conditions, and
 2. The composition of claim 1, wherein saidtherapeutic agent is methadone or its acid salts.
 3. The composition ofclaim 1, wherein the precipitating agent is an alkalinizing agent, andis present in an amount to achieve a pH within the range of 7.5 to 10when said composition is dissolved in water.
 3. combinations of (1) and(2).
 3. COMBINATIONS OF (1) AND (2).
 4. The composition of claim 3,wherein said alkalinizing agent is Na2HPO4.
 5. The composition of claim1, wherein the precipitating agenT is an alkalinizing agent whichprovides a pH in water solution of at least 6, and causes an increase ofpH to at least 7.5 upon heating or concentration of the solution.
 6. Thecomposition of claim 5, wherein said alkalinizing agent is NaHCO3. 7.The composition of claim 6 which also contains a solid food acid, theequivalent ratio of NaHCO3 to acid being substantially greater than 1.8. The composition of claim 7, wherein the equivalent ratio of NaHCO3 toacid is at least 1.89/1.
 9. The composition of claim 1, which furthercontains an ingestible solid additive providing increased viscosity uponconcentration of an aqueous solution of said composition.
 10. Thecomposition of claim 9, wherein the weight ratio of ingestible solidadditive to therapeutic agent ratio is within the range of 10:1 to 40:1.11. The composition of claim 1, wherein said precipitating agent isNaHCO3 and said therapeutic agent is methadone or its acid salts. 12.The composition of claim 6, wherein said composition is in tablet form.13. The composition of claim 12, wherein each tablet contains 40 mg ofmethadone hydrochloride.